| Size | Price | Stock | Qty |
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| 1mg |
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| Other Sizes |
| Targets |
Topoisomerase I
The compound does not directly target a therapeutic protein but is a substrate for bacterial beta-glucuronidase enzymes in the gut. These enzymes reactivate SN-38 glucuronide back to the active topoisomerase I inhibitor SN-38. It is also a substrate for the human UDP-glucuronosyltransferase UGT1A1 during its formation and hepatic clearance, making it a valuable probe for studying glucuronidation and de-glucuronidation processes. |
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| ln Vitro |
The glycoside hydrolases encoded by the human gut microbiome play an integral role in processing a variety of exogenous and endogenous glycoconjugates. Here we present three structurally and functionally distinct β-glucuronidase (GUS) glycoside hydrolases from a single human gut commensal microbe, Bacteroides uniformis We show using nine crystal structures, biochemical, and biophysical data that whereas these three proteins share similar overall folds, they exhibit different structural features that create three structurally and functionally unique enzyme active sites. Notably, quaternary structure plays an important role in creating distinct active site features that are hard to predict via structural modeling methods. The enzymes display differential processing capabilities toward glucuronic acid-containing polysaccharides and SN-38-glucuronide, a metabolite of the cancer drug irinotecan. We also demonstrate that GUS-specific and nonselective inhibitors exhibit varying potencies toward each enzyme. Together, these data highlight the diversity of GUS enzymes within a single Bacteroides gut commensal and advance our understanding of how structural details impact the specific roles microbial enzymes play in processing drug-glucuronide and glycan substrates[1].
As an inactive metabolite, SN-38 glucuronide itself does not exhibit direct antiproliferative activity. However, upon enzymatic hydrolysis by beta-glucuronidase enzymes from the human gut microbiome, it is converted back to the active moiety SN-38, which then inhibits DNA topoisomerase I (Topo I) with an IC50 of 0.077 microM for DNA synthesis inhibition. This reactivation is the primary mechanism of irinotecan-induced delayed diarrhea. |
| ln Vivo |
The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy[3].
The dose-limiting side effect of irinotecan therapy is severe, delayed-onset diarrhea caused by the reactivation of SN-38 glucuronide in the gut lumen via bacterial beta-glucuronidases. Oral administration of specific bacterial beta-glucuronidase inhibitors in mice was shown to protect against CPT-11-induced toxicity without harming commensal bacteria or the mammalian host enzyme, validating the critical role of this metabolite in irinotecan's gastrointestinal toxicity. |
| Enzyme Assay |
Irinotecan (CPT-11) is chemotherapy used mainly in the metastatic colorectal cancer. The purpose of this study was to develop and validate the LC-MS/MS for the simultaneous determination of CPT-11, SN-38, and SN-38G.
Methods: A 100 μL of plasma was prepared after protein precipitation and analyzed on a C18 column using 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile as mobile phases. The mass spectrometer worked with multiple reaction monitoring (MRM) in positive scan mode. The standard curves were linear on a concentration range of 5-10 000 ng/mL for CPT-11, 5-1000 ng/mL for SN-38, and 8-1000 ng/mL for SN-38G.
Results: In this assay, the intra and interday precision consisted of ≤9.11% and ≤11.29% for CPT-11, ≤8.70% and 8.31% for SN-38, and ≤9.90 and 9.64% for SN-38G.
Conclusion: This method was successfully used to quantify CPT-11, SN-38, and SN-38G and applied to a pharmacokinetic study[2].
A typical enzyme assay for this compound measures the activity of beta-glucuronidase. A reaction mixture containing purified recombinant beta-glucuronidase (e.g., from Bacteroides uniformis) or bacterial lysates, a fluorogenic substrate like 4-methylumbelliferyl-beta-D-glucuronide (4-MUG), and SN-38 glucuronide is prepared in assay buffer. After incubation at 37degC, the increase in fluorescence (for 4-MU) or the concentration of the released SN-38 (quantified by LC-MS/MS) is measured to determine enzyme activity and inhibition kinetics. |
| Cell Assay |
A cellular model for studying SN-38 glucuronide reactivation involves co-culturing human colon cancer cells with live anaerobic gut bacteria expressing beta-glucuronidase. The system is supplemented with SN-38 glucuronide, and bacterial reactivation leads to SN-38-mediated killing of the cancer cells, measured by viability assays. Alternatively, Caco-2 or HT-29 cells are used to study the transport and accumulation of SN-38 glucuronide in an intestinal epithelial barrier model.
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| Animal Protocol |
An in vivo mouse model is used to study CPT-11-induced intestinal toxicity. Female C57BL/6 mice are intravenously administered irinotecan (CPT-11) at a dose of 50 mg/kg for 4 consecutive days. The resulting gastrointestinal damage and diarrhea are mediated by the conversion of SN-38 glucuronide back to SN-38 by bacterial beta-glucuronidases. The efficacy of beta-glucuronidase inhibitors is evaluated by co-administering them orally to prevent this toxicity.
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| ADME/Pharmacokinetics |
SN-38 glucuronide is a polar, hydrophilic molecule that is efficiently eliminated via biliary excretion. This high polarity prevents its re-absorption from the gut lumen, making it the primary route for irinotecan detoxification. It is a substrate for the hepatic uptake transporter OATP1B1 and the efflux transporters MRP1, MRP2, and BCRP, which mediate its excretion into the bile, and is a key component of the enterohepatic recirculation pathway.
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| Toxicity/Toxicokinetics |
As an inactive endogenous metabolite, SN-38 glucuronide is not directly toxic to mammalian cells at physiological concentrations. Its toxicity is strictly associated with its conversion back to the potent cytotoxic agent SN-38 by bacterial enzymes within the gastrointestinal tract, which is the primary cause of the dose-limiting, delayed-onset diarrhea observed in patients treated with irinotecan.
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| References |
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| Additional Infomation |
SN38 glucuronide is a pyranoindoquinoline compound.
SN-38 glucuronide is a research-grade metabolite and is not a therapeutic agent. It serves as an essential chemical standard for developing LC-MS/MS assays for simultaneous quantification of irinotecan and its metabolites in plasma. Its discovery and characterization have been instrumental in understanding the microbiome's role in drug toxicity, leading to the development of bacterial beta-glucuronidase inhibitors as a potential strategy to mitigate irinotecan's side effects. As of now, it has not been approved for clinical use. |
| Molecular Formula |
C28H28N2O11
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|---|---|
| Molecular Weight |
568.53
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| Exact Mass |
568.169
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| Elemental Analysis |
C, 59.15; H, 4.96; N, 4.93; O, 30.95
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| CAS # |
121080-63-5
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| Related CAS # |
SN-38 glucuronide-13C6
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| PubChem CID |
443154
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| Appearance |
Off-white to yellow solid powder
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| Density |
1.7±0.1 g/cm3
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| Boiling Point |
1019.7±65.0 °C at 760 mmHg
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| Flash Point |
570.5±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.746
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| LogP |
-0.28
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
41
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| Complexity |
1190
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| Defined Atom Stereocenter Count |
6
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| InChi Key |
SSJQVDUAKDRWTA-CAYKMONMSA-N
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| InChi Code |
InChI=1S/C28H28N2O11/c1-3-12-13-7-11(40-26-22(33)20(31)21(32)23(41-26)25(35)36)5-6-17(13)29-19-14(12)9-30-18(19)8-16-15(24(30)34)10-39-27(37)28(16,38)4-2/h5-8,20-23,26,31-33,38H,3-4,9-10H2,1-2H3,(H,35,36)/t20-,21-,22+,23-,26+,28-/m0/s1
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| Chemical Name |
(2S,3S,4S,5R,6S)-6-(((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid
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| Synonyms |
SN-38 Glucuronide; 121080-63-5; SN38 glucuronide; SN-38G; SN-38-o glucuronide; D3XLA2EX2N; UNII-D3XLA2EX2N; CHEBI:8990;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~175.89 mM)
MEthanol : ~6.25 mg/mL (~10.99 mM) H2O : ~2.5 mg/mL (~4.40 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.40 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7589 mL | 8.7946 mL | 17.5892 mL | |
| 5 mM | 0.3518 mL | 1.7589 mL | 3.5178 mL | |
| 10 mM | 0.1759 mL | 0.8795 mL | 1.7589 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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